Correspondence

Induction of Fetal Hemoglobin in the Presence of Increased 3-Hydroxybutyric Acid Associated with β-Ketothiolase Deficiency

N Engl J Med 1994; 331:746-747September 15, 1994

Article

To the Editor:

Elevated levels of fetal hemoglobin may diminish the severity of the β-hemoglobinopathies sickle cell disease and β-thalassemia. In β-thalassemia, this effect is related to a reduction in the overall imbalance in the ratio of α-globin and non-α-globin chains. In sickle cell anemia, an elevated level of fetal hemoglobin results in a reciprocal decrease in the intracellular concentration of hemoglobin S and inhibits polymer formation. The discovery that butyric acid is an inducer of fetal hemoglobin arose from the observation that the switch from hemoglobin F to hemoglobin A is delayed in infants of diabetic mothers. In these newborns elevated plasma concentrations of a labile analogue of butyric acid, α-amino-n-butyric acid, were reported1.

Furthermore, in vivo and in vitro experiments have confirmed that butyrates are potent inducers of fetal-hemoglobin production2,3. On the basis of these findings, a phase 2 trial with arginine butyrate was carried out in a group of patients with thalassemia major and sickle cell disease4. This treatment led to a marked, although not consistent, rise in fetal-hemoglobin-containing reticulocytes and F-containing red cells, with an increase in the total hemoglobin level in one patient.

We recently saw a patient affected by a deficiency of 2-methylacetoacetyl-CoA-thiolase (β-ketothiolase),5 who had a marked increase in the fetal-hemoglobin level during an acute ketoacidotic episode. The patient was a three-year-old child who presented at our department with vomiting, ketonuria, and severe metabolic acidosis (pH, 7.16; bicarbonate, 7.2 mmol per liter; and base excess, -20.4 mmol per liter) after an upper respiratory tract infection. Gas chromatography and mass spectrometry showed increased urinary levels of 2-methyl-3-hydroxybutyric acid and tiglylglycine accompanied by substantially elevated levels of acetoacetic acid and 3-hydroxybutyric acid. The plasma amino acid and blood glucose levels were normal. Hemoglobin analysis carried out when the patient had severe acidosis and a plasma 3-hydroxybutyric acid level of 3.9 mmol per liter (normal range, 0.06 to 0.9) showed 13.5 percent fetal hemoglobin (Figure 1Figure 1Hemoglobin Analysis with the Use of High-Performance Liquid Chromatography during an Acute Ketoacidotic Episode (Left Panel) and after Metabolic Normalization (Right Panel) in a Three-Year-Old Child.), with normal values for mean corpuscular volume, mean corpuscular hemoglobin, and hemoglobin A. His parents had normal fetal-hemoglobin values (<1 percent). After correction of the acidosis and normalization of the 3-hydroxybutyric acid level, the fetal-hemoglobin level decreased to a normal value (0.5 percent). β-Thalassemia was not diagnosed on further follow-up.

This natural in vivo experiment confirms that butyrates are potent inducers of fetal hemoglobin. The marked induction of fetal-hemoglobin synthesis in this child was observed in the presence of a very high concentration of 3-hydroxybutyric acid and severe plasma acidosis. It is possible that other abnormal metabolites, which may be present in the serum but too unstable to be detected by our methods, aggravated the acidosis and induced the synthesis of fetal hemoglobin as well. This case also indicates that the induction of fetal hemoglobin requires the sustained presence of high plasma butyrate concentrations.

Renzo Galanello, M.D.
Antonio Cao, M.D.
University of Cagliari, 09100 Cagliari, Italy

Nancy Olivieri, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada

5 References

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Citing Articles (2)

Citing Articles

1. 1

   H. Bhatia, J. L. Hallock, A. Dutta, S. Karkashon, L. S. Sterner, T. Miyazaki, A. Dean, J. A. Little. (2009) Short-chain fatty acid-mediated effects on erythropoiesis in primary definitive erythroid cells. Blood 113:25, 6440-6448
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2. 2

   MARTIN H. STEINBERG, GRIFFIN P. RODGERS. (2001) Pharmacologic Modulation of Fetal Hemoglobin. Medicine 80:5, 328-344
   CrossRef